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PubMed2000

Chemoprotective and radioprotective effects of amifostine: an update of clinical trials.

Amifostine (Ethyol), the first broad-spectrum cytoprotectant approved in many countries for clinical use, is an analog of cysteamine and was originally developed by the U.S. Walter Reed Army Institute of Research in the 1950s as a radioprotective agent. Studies have shown that amifostine selectively protects normal tissues of various organs from the effects of radiation and multiple cytotoxic chemotherapeutic drugs. Amifostine has demonstrated broad-spectrum cytoprotection against myelotoxicity, nephrotoxicity, xerostomia, and mucositis associated with various chemotherapy and radiation modalities. Amifostine has been evaluated in large comparative clinical trials in patients with advanced ovarian cancer, rectal cancer, and head and neck cancer, and in many phase 2 trials in patients with various neoplastic diseases. These trials have shown that amifostine delivers protection from the cytotoxic effects of cisplatin, cyclophosphamide, and radiation on various organs. Pretreatment with amifostine has also improved salivary gland tolerance of high-dose radioiodine treatment. Recent unique observations include improvement in cytopenia in patients with myelodysplastic syndrome. This review summarizes preclinical and clinical data on amifostine and includes trials that evaluated the drug's chemoprotective and radioprotective effects and other potential uses in clinical oncology.

Amifostine↗
PubMed2002

The neuronal apoptosis inhibitory protein is a direct inhibitor of caspases 3 and 7.

The neuronal apoptosis inhibitory protein (NAIP) was identified as a candidate gene for the inherited neurodegenerative disorder spinal muscular atrophy. NAIP is the founding member of a human protein family that is characterized by highly conserved N-terminal motifs called baculovirus inhibitor of apoptosis repeats (BIR). Five members of the human family of inhibitor of apoptosis proteins including NAIP have been shown to be antiapoptotic in various systems. To date, a mechanism for the antiapoptotic effect of NAIP has not been elucidated. To investigate NAIP function, we found cytoprotection of NAIP-expressing primary cortical neurons treated to undergo caspase-3-dependent apoptosis. The additional treatment of these neurons with the pancaspase inhibitor boc-aspartyl(OMe)-fluoromethylketone did not result in increased survival. Similar cytoprotective effects were obtained using HeLa cells transiently transfected with a NAIP N-terminal construct and treated to undergo a caspase-3-dependent cell death. To examine whether NAIP inhibits caspases directly, recombinant N-terminal NAIP protein containing BIR domains was overexpressed, purified, and tested for caspase inhibition potential. Our results demonstrate that inhibition of caspases is selective and restricted to the effector group of caspases, with K(i) values as low as approximately 14 nm for caspase-3 and approximately 45 nm for caspase-7. Additional investigations with NAIP fragments containing either one or two NAIP BIRs revealed that the second BIR and to a lesser extent the third BIR alone are sufficient to mediate full caspase inhibition.

Animals↗
PubMed2002

Retinal pigment epithelium is protected against apoptosis by alphaB-crystallin.

PURPOSE: The degeneration of retinal pigment epithelial (RPE) cells is considered to be a crucial event in the pathophysiology of age-related macular degeneration (AMD). Cumulative oxidative damage has been implicated in the development of the changes seen in AMD. The present study was undertaken to evaluate the expression of the small heat shock protein alphaB-crystallin in the RPE in response to oxidative stress and to explore whether alphaB-crystallin expression confers an antiapoptotic cytoprotective effect on RPE cells. METHODS: Native human RPE cells from the macula and retinal periphery were analyzed by RT-PCR and Western blot analysis for expression of alphaB-crystallin. Monolayer cultures of human RPE cells were stressed by heat shock (42 degrees C for 20 minutes) or oxidant-mediated injury (50-300 micro M H(2)O(2) for 1 hour). Induction of alphaB-crystallin and the corresponding mRNA was assessed by Western and Northern blot analyses. To study the cytoprotective effect of alphaB-crystallin, human RPE cells were transfected with either a neomycin-selectable expression vector containing alphaB-crystallin cDNA or a control vector without alphaB-crystallin cDNA. Caspase-3 activity was determined by observing the cleavage of a colorimetric peptide substrate. Cell viability was quantified by combined propidium iodide and Hoechst 33342 staining. RESULTS: alphaB-crystallin is constitutively expressed in RPE under in vivo and in vitro conditions. Western blot analysis of freshly isolated RPE showed greater baseline expression levels in RPE derived from the macular area than in that from the more peripheral regions. Heat shock treatment and oxidative stress caused a significant increase in alphaB-crystallin mRNA and protein. Oxidant-mediated injury in RPE cells with baseline expression levels of alphaB-crystallin resulted in apoptotic cell death, as measured by caspase-3 activity, whereas RPE cells that had been stably transfected with alphaB-crystallin were more resistant to H(2)O(2)-induced cellular injury. CONCLUSIONS: alphaB-crystallin may function as a stress-inducible antiapoptotic protein in human RPE and is inducible by oxidative stress, a condition implicated in the pathogenesis of AMD. Overexpression of alphaB-crystallin may be an important mechanism for the RPE to prevent apoptotic cell death in response to cellular stress.

Adolescent↗
PubMed2003

[Radiation protectants of the crystalline lens].

During more than a half of century, numerous compounds have been tested in different models against radiation-induced cataract. In this report, we will review the radioprotectors that have been already tested for non-human crystalline lens protection. We will focus on the most important published studies in this topic and the mechanisms of cytoprotection reported in vitro and in vivo from animals. The most frequent mechanisms incriminated in the cytoprotective effect are: free radical scavenging, limitation of lipid peroxidation, modulation of cycle progression increase of intracellular reduced glutathion pool, reduction of DNA strand breaks and limitation of apoptotic cell death. Amifostine (or Ethyol) and anethole dithiolethione (or Sulfarlem), already used clinically as chemo- and radioprotectants, could be further tested for ocular radioprotection particularly for radiation-induced cataract.

Amifostine↗
PubMed2005

Role of prostaglandins in gastroprotection and gastric adaptation.

Since Robert discovery that pretreatment with prostaglandin (PG) applied in non-antisecretory dose can prevent the injury of gastric mucosa induced by necrotizing agents, much attention was paid to the role of these cyclooxygenase (COX) products in the mechanism of gastric mucosal integrity and ulcer healing. The ability of exogenous PG to attenuate or even completely prevent mucosal damage caused by corrosive substances such as absolute ethanol, hyperosmolar solutions or concentrated bile has been termed "cytoprotection". Increased generation of endogenous PG in the gastric mucosa exposed to the topical contact with "mild irritant" such as 20% ethanol, 1 mM NaCl or 5 mM taurocholate also prevented gastric injury caused by strong irritants via phenomenon of adaptive cytoprotection. Other mediators such as growth factors, nitric oxide (NO) or calcitonin gene related peptide (CGRP) as well as some gut hormones including gastrin and cholecystokinin (CCK), leptin, ghrelin and gastrin-releasing peptide (GRP) have been also found to protect gastric mucosa against the damage induced by corrosive substances. This protective action of gut hormones has been attributed to the release of PG or activation of sensory nerves because it could be abolished by the pretreatment with indomethacin or large neurotoxic dose of capsaicin and restored by the addition of exogenous PGE(2) or CGRP, respectively. Short (5 min) ischemia of the stomach applied before prolonged ischemia-reperfusion (I/R) attenuated markedly the gastric lesions produced by this I/R and also prevented the mucosal damage provoked by necrotizing substances. This protection could be abolished by the pretreatment with non-steroidal anti-inflammatory drugs (NSAID) and was accompanied by an enhancement of gastric mucosal COX-2 expression and activity. Exposure of gastric mucosa to single insult of acidified aspirin (ASA) causes severe mucosal damage with occurrence of multiple haemorrhagic lesions but with repeated application of ASA, the attenuation of mucosal lesions is observed, despite the profound inhibition of PGE(2) generation. This phenomenon called "gastric adaptation" does not appear to depend upon endogenous biosynthesis of PG but possibly involves enhanced production of growth factors increasing cell proliferation and mucosal regeneration. Unlike short lived gastroprotection by PG, NO, CGRP, mild irritants or short ischemia, gastric adaptation appears to be long-lasting phenomenon accompanied by increased resistance of the adapted mucosa to subsequent damage induced by corrosive agents.

Animals↗
PubMed2006

Protection of human islets from induction of apoptosis and improved islet function with HO-1 gene transduction.

BACKGROUND: Islet transplantation represents an ideal therapeutic approach for treatment of type 1 diabetes but islet function and regeneration may be influenced by necrosis or apoptosis induced by oxidative stress and other insults. Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in the catabolism of heme into biliverdin, releasing free iron and carbon monoxide. It has also been reported to be an antioxidant enzyme which can improve the function of grafted islets by cytoprotection via free radical scavenging and apoptosis prevention. In the present study, we investigated whether transduction of HO-1 genes into human islets with an adenovirus vector has cytoprotective action on islets cultured in vitro and discuss this method of gene therapy for clinical islet transplantation. METHODS: Cadaveric pancreatic islets were isolated and purified in vitro. Transduction efficiency of islets was determined by infecting islets with adenovirus vector containing the enhanced green fluorescent protein gene (Ad-EGFP) at multiplicities of infection (MOI) of 2, 5, 10, or 20. Newly isolated islets were divided into three groups: EGFP group, islets transduced with Ad-EGFP using MOI = 20; HO-1 group, transduced with adenovirus vectors containing the human HO-1 gene using MOI = 20; and control group, mock transduced islets. Insulin release after glucose stimulation of the cell lines was determined by a radioimmunoassay kit and the stimulation index was calculated. Flow cytometry was used to detect apoptotic cells in the HO-1 group and in the control group after induction by recombinant human tumor necrosis factor-alpha (rTNFalpha) and cycloheximide (CHX) for 48 hours. RESULTS: Adenovirus vectors have a high efficiency of gene transduction into adult islet cells. Transduction of islets with the Ad-EGFP was most successful at MOI 20, at which MOI fluorescence was very intense on day 7 after transduction and EGFP was expressed in cultured islet cells for more than four weeks in vitro. The insulin release in the control group was (182.36 +/- 58.96) mIU/L after stimulation by high glucose media (16.7 mmol/L), while insulin release from the HO-1 group and the EGFP group were (270.09 +/- 89.37) mIU/L and (175.95 +/- 75.05) mIU/L respectively. Compared to the control group and the EGFP group, insulin release in the HO-1 group increased significantly (P < 0.05). After treatment with rTNFalpha and CHX the apoptotic ratio of islet cells was (63.09 +/- 10.86)% in the HO-1 group, significantly lower than (90.86 +/- 11.25)% in the control group (P < 0.05). CONCLUSIONS: Transduction of human islets with Ad-HO-1 can protect against TNF-alpha and CHX mediated cytotoxicity. The HO-1 gene also appears to facilitate insulin release from human islets. Transduction of donor islets with the adenovirus vector containing an HO-1 gene might have potential value in clinical islet transplantation.

Adenoviridae↗
PubMed1997

[Involvement of nitric oxide and cGMP in the protective effect of neurotensin on hepatocytes].

In the present work, the relation of cytoprotection of neurotensin to nitric oxide (NO), cGMP and cAMP was investigated in primary cultured mouse hepatocytes. The results are as follows: After administration of acetaminophen (20 mmol/L) to the medium, the leakage of GOT and GPT increased significantly. Pretreatment with neurotensin (10(-7) mol/L) before acetaminophen reduced the leakage of GOT and GPT. No synthase inhibitor, L-NAME, completely blocked the cytoprotective effect of neurotensin. Neurotensin could enhance the intracellular cGMP content, but had no effect on cAMP content. These results indicate that the protective effect of neurotensin on hepatocytes is mediated by NO probably by enhancing intracellular cGMP content.

Acetaminophen↗
PubMedDate not supplied

Effect of adequate alcohol intake, with or without cigarette smoking, on the risk of Helicobacter pylori infection.

BACKGROUND/AIMS: Chronic adequate alcohol intake induces an "adaptive cytoprotection", mediated by endogenous release of prostaglandins and increased activity of gastric antioxidants, that reduces the mucosal damage caused by higher ethanol concentrations. The aim of our study was to verify the presence of a protection against Helicobacter pylori infection, induced by adequate alcohol consumption, with or without cigarette smoking. METHODOLOGY: We studied 303 consecutive dyspeptic patients, who underwent gastroscopy for the first time. The patients were allocated to four groups: A) 57 with adequate alcohol consumption; B) 88 smokers pts; C) 64 smokers pts with adequate alcohol consumption; D) 93 non-smokers and teetotalers. RESULTS: H. pylori infection was found in 32 pts of group A (56.14%), 67 of group B (77.13%), 46 of group C (71.87%) and 61 of group D (65.69%). There was a statistical significant difference in H. pylori-positivity only between group A and group B (p=0.019). CONCLUSIONS: Even if we noted a statistical difference only between group A and B, however the lower prevalence of H. pylori infection in group A than in other groups suggests a protective mechanism of adequate alcohol consumption, mediated by "adaptive cytoprotection", which reduces the risk of H. pylori infection.

Adolescent↗
PubMedDate not supplied

Magaldrate stimulates endogenous prostaglandin E2 synthesis in human gastric mucosa in vitro and in vivo.

BACKGROUND/AIMS: Prostaglandin E2 (PGE2) plays an important role in the inhibition of gastric acid production and exerts cytoprotective action. The in vitro and in vivo effect of magaldrate, an aluminum containing antacid, on PGE2 synthesis in the gastric mucosa was investigated. METHODOLOGY: In the first part of the study, magaldrate was added to a suspension of isolated gastric mucosal cells. In the second part, the antacid gel was applied to the gastric mucosa during gastroscopy and biopsies were taken from the same site 5 and 10 min later. RESULTS: The antacid significantly stimulated PGE2 release from the suspension of isolated gastric cells in vitro. The biopsies obtained after the application of magaldrate showed an increased PGE2 production compared to specimens obtained before. CONCLUSIONS: The data suggest that in addition to its neutralizing capacity as an antacid, magaldrate contributes to the cytoprotective activity of the mucosa by stimulating endogenous PGE2 synthesis.

Adult↗
PubMed1990

Vagotomy effect on gastric prostaglandins. Primarily neural or secondary to hypoacidity?

Prostaglandins have been implicated in gastric mucosal cytoprotection. Vagotomy results in both cytoprotection and increased mucosal prostaglandin concentrations. However, the mechanism by which vagotomy affects prostaglandin generation remains unknown. In this study we compared vagotomy with long-term acid suppression using anticholinergic (atropine sulfate) or histamine2-receptor antagonism (cimetidine) and assessed mucosal injury and prostaglandin generation during graded stress. Vagotomy correlated with decreases in injury only in severe stress, while both atropine and cimetidine decreased injury also during moderate stress. Prostaglandin generation decreased in all groups during severe stress. Compared with sham operation, vagotomy, atropine, and cimetidine were all associated with increased mucosal prostaglandin generation in all stress periods. During severe stress, both atropine and cimetidine also evidenced higher prostaglandin generation than did vagotomy. These results suggest that vagotomy primarily decreases acid secretion, which then secondarily results in increased mucosal generation.

Animals↗
PubMed1997

Induction of myocardial heat shock protein 70 during cardiac surgery.

Animal experiments have shown that members of the heat shock protein (HSP) family have cytoprotective properties against ischaemia. In experimentally induced cardiac ischaemia, the induction of HSP70s correlates with reduced infarct size and enhanced myocardial function and endothelial recovery. Direct evidence that increased myocardial HSP70 expression result in cytoprotection during ischaemia has also been obtained using transgenic mice overexpressing either rat or human HSP72. This study examined the induction and expression of myocardial HSP70s after an obligatory period of ischaemia in patients during cardiac surgery. The level of HSP72/HSC73 protein in Tru-cut biopsies of the myocardium, taken before and after an acute ischaemic insult, was examined using a polyclonal antibody. The amount of HSP72 mRNA in the biopsies was also determined by reverse transcriptase polymerase chain reaction (RT-PCR) and correlated HSP72/HSC73 protein expression. In four patients subjected to brief alternating periods of normothermic ischaemia and reperfusion, the amount of myocardial HSP72/HSC73 protein was increased several fold after ischaemic insult. This was accompanied by increased expression of HSP72 mRNA. In contrast, the amounts of myocardial HSP72/HSC73 protein and HSP72 mRNA were unchanged in a patient subjected to a single prolonged period of hypothermic ischaemia. Given the proven myocardial protective properties of HSP72 in experimental models, it is postulated that the observed induction of HSP72 may have a similar function in man.

Biopsy↗
PubMed1996

Differential expression of the heavy-chain ferritin gene in non-adhered and adhered oligodendrocytes.

Oligodendrocytes (OLGs) synthesize and maintain central nervous system myelin. Little is known about the molecules and pathways involved in signaling the commencement of myelination; yet myelination is spatially and temporally controlled. We are interested in deciphering the signaling events that control the on and off switch of myelination. To address these questions we are using an in vitro model system consisting of pure cultures of OLGs, isolated from postmyelination brains. We have shown that in vitro, these OLGs regenerate and reenact the ontogenic development of myelin upon adhesion to a substratum; we have also shown that when transplanted in vivo, they can form myelin. Hence, identifying the genes that are turned on upon OLG adhesion seemed a worthwhile approach to singling out those genes that are critical to the differentiation process. For this we adopted a novel technique-differential display-that permits the comparison of gene expression under two sets of conditions; in our case between non-adhered and adhered OLGs. Using the differential display method in conjunction with a set of five arbitrary primers, we have identified five cDNAs that are activated upon OLG substratum adhesion. Four of these cDNAs proved to be fragments of the heavy (H)-chain ferritin cDNA. H-chain ferritin is involved in the rapid sequestration and delivery of iron; it is also a cytoprotectant. Brain iron is localized predominantly in OLGs. Our finding that the expression of H-chain ferritin is upregulated upon OLG regeneration/differentiation agrees with reports, in other cell types, that H-chain ferritin transcription is modulated by factors that control cell growth and differentiation. The enhanced transcription results in a twofold augmentation in ferritin synthesis. This is the first demonstration of an adherence-mediated activation of the H-chain ferritin gene. The observation has interesting implications. The transcription of the H-chain ferritin gene is associated with tissue stress such as might occur during rapid cell growth. The fact that this transcription takes place upon OLG-substratum adhesion can be viewed as another manifestation of the anchorage-induced signal that drives OLGs toward a differentiation program. This entails the synthesis of all the necessary components for the assembly of large quantities of membranes, hence constituting a period of rapid growth and considerable cell stress. We have sequenced the full-length ferritin cDNA of ovine OLGs; the cDNA is 775 bp long. The coding sequence starts at residue 57 with the ATG codon and terminates at residue 602, with the stop codon TAA. The cDNA codes for 181 amino acids with a predicted size for the protein of 22 kD. The deduced amino acid sequence is 93% identical to human ferritin. We postulate that OLG H-chain ferritin may function at more than one level: 1) it provides the iron required to sustain an oxidative metabolism; and 2) it acts as a cytoprotectant against oxidant-mediated injury.

Amino Acid Sequence↗
PubMed2003

Heat shock factor 1-independent activation of dendritic cells by heat shock: implication for the uncoupling of heat-mediated immunoregulation from the heat shock response.

The induction of heat shock proteins by heat shock is classically defined as the heat shock response, which is involved in cytoprotection, inflammation and immune responses. Whereas the cytoprotective properties of heat shock have been well characterized, the immunomodulating roles of the heat shock response on the immune system are just emerging. In particular, it is not known whether immunomodulating functions of heat are mediated by the heat shock response. We addressed this question genetically, using a murine model that is unable to mount the heat shock response because of deletion of a major transcriptional factor, heat shock factor 1 (Hsf1). We focused on the roles of heat shock on modulating the functions of dendritic cells (DC) because of their important roles in both innate and adaptive immunity. We found that heat shock matures CD11c(+) DC both in vitro and in vivo, phenotypically and functionally, in the absence of any exogenous inflammatory stimuli. Furthermore, heat-shock-mediated DC maturation is independent of Hsf1, as Hsf1(-/-) DC can be matured by heat shock equally well as wild-type DC. Our novel findings demonstrate that heat shock, one of the most primitive biological responses, can modulate the immune response without the requirement for the transcriptional induction/repression of target genes mediated by Hsf1.

Animals↗
PubMed2005

Activation of the Nrf2/antioxidant response pathway increases IL-8 expression.

Oxidant stress can initiate or enhance inflammatory responses during tissue injury, possibly through activation of redox-sensitive chemokines. Because the transcription factor Nrf2 (NF-E2-related factor 2) is responsive to oxidative stress, and induces expression of cytoprotective and antioxidant genes that attenuate tissue injury, we postulated that Nrf2 may also regulate chemokine expression. To test this hypothesis, Nrf2 expression was directly increased in primary human kidney mesangial cells and aortic endothelial cells, or cell lines with an adenoviral construct, and the effects on the pro-inflammatory chemokine interleukin-8 (IL-8) were assessed. Nrf2 expression significantly increased IL-8 mRNA levels and protein secretion. Nrf2 caused only a weak induction of IL-8 transcription, but significantly increased the half-life of IL-8 mRNA. These data demonstrate that activation of the Nrf2/antioxidant response pathway induces expression of IL-8. The dominant mechanism of Nrf2-mediated IL-8 induction is through mRNA stabilization. Considering the evidence that Nrf2 activation is mainly cytoprotective, these observations raise the possibility that under certain circumstances IL-8 may serve an anti-inflammatory role and thereby contribute to the resolution of tissue injury.

Antioxidants↗
PubMed2006

Constitutive androstane receptor (CAR) ligand, TCPOBOP, attenuates Fas-induced murine liver injury by altering Bcl-2 proteins.

The constitutive androstane receptor (CAR) modulates xeno- and endobiotic hepatotoxicity by regulating detoxification pathways. Whether activation of CAR may also protect against liver injury by directly blocking apoptosis is unknown. To address this question, CAR wild-type (CAR+/+) and CAR knockout (CAR-/-) mice were treated with the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) and then with the Fas agonist Jo2 or with concanavalin A (ConA). Following the administration of Jo2, hepatocyte apoptosis, liver injury, and animal fatalities were abated in TCPOBOP-treated CAR+/+ but not in CAR-/- mice. Likewise, acute and chronic ConA-mediated liver injury and fibrosis were also reduced in wild-type versus CAR(-/-) TCPOBOP-treated mice. The proapoptotic proteins Bak (Bcl-2 antagonistic killer) and Bax (Bcl-2-associated X protein) were depleted in livers from TCPOBOP-treated CAR+/+ mice. In contrast, mRNA expression of the antiapoptotic effector myeloid cell leukemia factor-1 (Mcl-1) was increased fourfold. Mcl-1 promoter activity was increased by transfection with CAR and administration of TCPOBOP in hepatoma cells, consistent with a direct CAR effect on Mcl-1 transcription. Indeed, site-directed mutagenesis of a putative CAR consensus binding sequence on the Mcl-1 promoter decreased Mcl-1 promoter activity. Mcl-1 transgenic animals demonstrated little to no acute liver injury after administration of Jo2, signifying Mcl-1 cytoprotection. In conclusion, these observations support a prominent role for CAR cytoprotection against Fas-mediated hepatocyte injury via a mechanism involving upregulation of Mcl-1 and, likely, downregulation of Bax and Bak.

Animals↗
PubMed1997

Glycine protects against hepatocyte killing by KCN or hypoxia by preventing intracellular Na+ overload in the rat.

Glycine has been shown to prevent hepatocyte death induced by anoxia and by several toxic agents. However, the mechanisms responsible for such a cytoprotective effect have not yet been entirely clarified. We have previously shown that an uncontrolled increase in intracellular Na+ is critical for hepatocyte killing induced by adenosine triphosphate (ATP) depletion. We herein report that protection by glycine (2 mmol/L) against cytotoxicity induced in isolated rat hepatocyte by potassium cyanide (KCN) or hypoxia was associated with the prevention of cytosolic Na+ accumulation. The addition of the Na+ ionophore, monensin, abolished the effects of glycine on both Na+ increase and cytotoxicity. Pretreating hepatocytes with the glycine-receptor antagonist, strychnine (1 mmol/L), similarly prevented Na+ overload and cell killing. Glycine at high concentrations and strychnine are known to block Cl- channels in many cell types. Consistently, we have observed that glycine and strychnine prevented the increase of intracellular Cl- levels caused by hypoxia or KCN. Incubation of hepatocytes in a Cl(-)-free medium, obtained by substituting chloride with membrane-impermeable gluconate, significantly reduced Na+ accumulation and cell killing triggered by hypoxia or KCN. Both these effects were abolished by the addition of monensin. The cytoprotective action exerted by hepatocyte incubation in the Cl(-)-free medium was, however, lost when membrane-permeable nitrate, which allowed Na+ accumulation, was used instead to replace chloride. Altogether, these results indicate that glycine inhibition of Cl- conductance protects against hepatocyte killing induced by KCN and hypoxia by interfering with intracellular Na+ accumulation triggered by ATP depletion.

Animals↗
PubMed1998

Cyclic adenosine monophosphate-mediated protection against bile acid-induced apoptosis in cultured rat hepatocytes.

UNLABELLED: Cyclic adenosine monophosphate (cAMP) has been shown to modulate apoptosis. To evaluate the role of cAMP in bile acid-induced hepatocyte apoptosis, we studied the effect of agents that increase cAMP on the induction of apoptosis by glycochenodeoxycholate (GCDC) in cultured rat hepatocytes. GCDC induced apoptosis in 26.5%+/-1.1% of hepatocytes within 2 hours. Twenty-minute pretreatment of hepatocytes with 100 micromol/L 8-(4-chlorothiophenyl) cAMP (CP-cAMP) resulted in a reduction in the amount of apoptosis to 35.2%+/-3.8% of that seen in hepatocytes treated with GCDC alone. Other agents that increase intracellular cAMP, including dibutyryl cAMP (100 micromol/L), glucagon (200 nmol/L), and a combination of forskolin (20 micromol/L) and 3-isobutyl-1-methylxanthine (20 micromol/L), also inhibited GCDC-induced apoptosis to a similar extent. Pretreatment with the protein kinase A (PKA) inhibitor, KT5720, prevented the protective effect of CP-cAMP and inhibited CP-cAMP-induced activation of PKA activity. Inhibitors of phosphatidylinositol 3-kinase (PI3K), wortmannin (50 nmol/L), or Ly 294002 (20 micromol/L) also prevented the cytoprotective effect of cAMP. PI3K assays confirmed that wortmannin (50 nmol/L) inhibited PI3K activity, while CP-cAMP had no effect on the activity of this lipid kinase. GCDC increased mitogen-activated protein kinase (MAPK) activity, but had no effect on stress-activated protein kinase (SAPK) activity in hepatocytes. cAMP decreased basal and GCDC-induced MAPK activity and increased SAPK activity. The MAPK kinase inhibitor, PD 98059, inhibited both GCDC-mediated MAPK activation and GCDC-induced apoptosis. IN CONCLUSION: 1) agents that increase intracellular cAMP protect against hepatocyte apoptosis induced by hydrophobic bile acids; 2) activation of MAPK by GCDC may be involved in bile acid-induced apoptosis; and 3) cAMP-mediated cytoprotection against bile acid-induced apoptosis appears to involve PKA, MAPK, and PI3K.

Androstadienes↗
PubMed2007

Prostaglandin E(2) protects human lung fibroblasts from cigarette smoke extract-induced apoptosis via EP(2) receptor activation.

Prostaglandin E(2) (PGE(2)) has been shown to have a strong cytoprotective effect, inhibiting apoptosis. In the present study, we evaluated whether PGE(2) has a protective effect on cigarette smoke extract (CSE)-induced apoptosis in human lung fibroblasts. Apoptosis was assessed by various methods, including DNA content analysis. CSE (15%-20%) led to apoptosis and induced imbalance in favor of pro- over anti-apoptotic protein expression and activated caspases. PGE(2) blocked CSE-induced apoptosis and modulated the balance of pro- and anti-apoptotic proteins and decreased the activation of caspases. This anti-apoptotic effect was mediated via EP(2) receptor activation as the EP(2) agonist butaprost mimicked PGE(2) activity and siRNA for the EP(2) receptor blocked it. An adenylyl cyclase inhibitor was found to abolish the PGE(2)-mediated cytoprotective effect. Correspondingly, c-AMP analogs blocked CSE-induced apoptosis. Consistently, the protein kinase A (PKA) inhibitor KT-5720 abolished PGE(2)-mediated protection. PGE(2) and butaprost phosphorylated Bad and KT-5720 blocked phosphorylation. These results suggest that PGE(2) inhibits CSE-induced apoptosis via EP(2) receptor activation and activation of PKA, which leads to an alteration in the balance between pro- and anti-apoptotic factors. Through such a mechanism, PGE(2) may alter survival of cells in the smoke-exposed lungs, thus affecting the pathogenesis of cigarette smoke-induced disease.

Adenylyl Cyclase Inhibitors↗